The increasingly common problem of COPD has been related to numerous extrinsic factors. Relatively little is known about host factors. Low alpha 1 antitrypsin levels explain only a small portion of cases. Recent demonstration of variation in leukocyte elastase activity among individuals suggests that protease/antiprotease relationship may be an important host mechanism. We recently studied 111 index subjects with COPD and 111 controls with demonstrated normal pulmonary function matched for age cohort, sex, smoking history, and occupation. With these predisposing factors matched, other host factors were analyzed; genetic, immunologic, and endocrine characteristics. Among the serum immunoglobulins, IgD was significantly higher in index cases as were IgD and IgM immunoglobulins in nasal secretions. Serum components of complement C3 and C4 were significantly lower in index cases than controls. Recent studies have shown that leukocyte elastase consumes complement, reducing serum levels. Predisposition to COPD has been shown in homozygote deficient alpha 1 antitrypsin cases. Since alpha 1 antitrypsin specifically neutralizes leukocyte elastase and homozygote deficient cases are uncommon (3 ZZ's in our index group) in proportion to the total number of cases of COPD, high levels of leukocyte elastase could be a predisposing factor in subjects with more normal levels of alpha 1 antitrypsin. Since our subjects showed lower complement than controls, this finding reflects high leukocyte elastase activity. We propose to study leukocyte elastase and protease/antiprotease complexes in our index subjects, matched controls, and closest sibling of the same sex of index and controls subjects whom we have already studied. We would plan to measure the pulmonary function to determine the three year decrement in values and compare these to the leukocyte elastase values and to other risk factors we have reported. The decrement in function may be a more sensitive measure of the pathogenesis of disease than a cross sectional study of these groups.